tbuckley/cabot-search huggingface dataset:
Fracture incidence in children after developing atopic dermatitis: A Korean nationwide birth cohort study
Authors: Seung Won Lee, Youn Ho Shin, Jae Il Shin, So Min Kang, Katrina Abuabara, Jimin Hwang, Jung U. Shin, Hyungrye Noh, Sunyeup Kim, Chan Yeong Heo, Ai Koyanagi, Louis Jacob, Lee Smith, Jonas F. Ludvigsson, Stephen Turner, Ju‐Young Shin, Han Eol Jeong, Jung‐Hyun Kim, Sang Youl Rhee, Dong In Suh, Dong Keon Yon, Seong Ho Cho
Journal: Allergy (2022)
Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome
Authors: Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine Steele, Amy Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Journal: Journal of Clinical Investigation (2022)

BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1β and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.
Selective Formation of Osteogenic and Vasculogenic Tissues for Cartilage Regeneration
Authors: Zeyang Liu, Haochen Nan, Yi Shiou Chiou, Zhen Zhan, Peter E. Lobie, Chengzhi Hu
Journal: Advanced Healthcare Materials (2022)

Abstract Tissue‐engineered periosteum substitutes (TEPSs) incorporating hierarchical architecture with osteoprogenitor and vascular niches are drawing much attention as a promising tool to support functional cells in defined zones and nourish the cortical bone. Current TEPSs usually lack technologies to closely observe cell performance, especially at the cell contact interface between distinct compartments containing defined biological configurations and functions. Here, an electrodeposition strategy is reported, which enables the selective formation of TEPSs with osteoprogenitor and vascular niches in a multiphasic scaffold in combination with different human cell types for cartilage regeneration in an in vivo osteochondral defect model. Human umbilical vein endothelial cells (HUVECs), dermal fibroblasts (HDFs), and bone marrow mesenchymal stem cells (hMSCs) are used to mirror both the vascular and osteogenic niches, respectively. It is observed that the intrinsic viscoelastic nature of the porous solid matrix is essential to successfully induce angiogenesis. Coculture of hMSCs with functional cells (HUVECs/HDFs) in TEPSs also effectively promoted periosteal regeneration, including osteogenic and angiogenic processes. The osteoarthritis cartilage histopathology assessment and histologic/histochemical grading system data indicate that the TEPSs containing hMSCs/HUVECs/HDFs exhibit superior potential for cartilage regeneration.
Single Seminal Vesicle Metastasis From Dorsal Melanoma Detected by 18F-FDG PET/CT and Confirmed by Biopsy
Authors: Nathalie Testart Dardel, Elsa Isenborghs, Massimo Valerio, Olivier Michielin, Niklaus Schaefer
Journal: Clinical Nuclear Medicine (2022)

This case shows an unusual presentation of a melanoma metastasis, visualized by 18 F-FDG digital PET/CT, with a single abnormal focal uptake in the right seminal vesicle. Histologic analysis confirmed a melanoma metastasis, subsequently treated by stereotactic radiation therapy. We illustrate an unusual and single-site millimetric melanoma metastasis detected by 18 F-FDG PET/CT, highlighting the high performance of state-of-the-art digital PET/CT and the importance of a multidisciplinary approach in treatment and follow-up of melanoma patients. In this case, histological diagnosis was essential for correct diagnosis and adequate clinical management of the patient.
Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification
Authors: Yufei Chen, Chenfeng Mao, Rui Gu, Rujia Zhao, Weihao Li, Zihan Ma, Yiting Jia, Fang Yu, Jian Luo, Yi Fu, Jinpeng Sun, Wei Kong
Journal: Circulation Research (2022)

Background: Vascular calcification is closely related to the all-cause mortality of cardiovascular events. Basement membrane protein nidogen-2 is a key component of the vascular extracellular matrix microenvironment and we recently found it is pivotal for the maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). However, whether nidogen-2 is involved in VSMCs osteochondrogenic transition and vascular calcification remains unclear. Methods: VSMCs was treated with high-phosphate to study VSMC calcification in vitro. Three different mice models (5/6 nephrectomy-induced chronic renal failure, cholecalciferol-overload, and periadventitially administered with CaCl 2 ) were used to study vascular calcification in vivo. Membrane protein interactome, coimmunoprecipitation, flow cytometric binding assay, surface plasmon resonance, G protein signaling, VSMCs calcium assays were performed to clarify the phenotype and elucidate the molecular mechanisms. Results: Nidogen-2 protein levels were significantly reduced in calcified VSMCs and aortas from mice in different vascular calcification model. Nidogen-2 deficiency exacerbated high-phosphate-induced VSMC calcification, whereas the addition of purified nidogen-2 protein markedly alleviated VSMC calcification in vitro. Nidogen-2 -/- mice exhibited aggravated aorta calcification compared to wild-type (WT) mice in response to 5/6 nephrectomy, cholecalciferol-overload, and CaCl 2 administration. Further unbiased coimmunoprecipitation and interactome analysis of purified nidogen-2 and membrane protein in VSMCs revealed that nidogen-2 directly binds to LGR4 (leucine-rich repeat G-protein-coupled receptor 4) with K D value 26.77 nM. LGR4 deficiency in VSMCs in vitro or in vivo abolished the protective effect of nidogen-2 on vascular calcification. Of interest, nidogen-2 biased activated LGR4-Gαq-PKCα (protein kinase Cα)-AMPKα1 (AMP-activated protein kinase α1) signaling to counteract VSMCs osteogenic transition and mineralization. Conclusions: Nidogen-2 is a novel endogenous ligand of LGR4 that biased activated Gαq- PKCα-AMPKα1 signaling and inhibited vascular calcification.
Estimating the total incidence of type 1 diabetes in children and adolescents aged 0–19 years from 1990 to 2050: a global simulation-based analysis
Authors: Zachary J Ward, Jennifer M Yeh, Che L Reddy, Apoorva Gomber, Carlo Ross, Thanitsara Rittiphairoj, Jennifer Manne-Goehler, Asmahan T Abdalla, Mohamed Ahmed Abdullah, Abdurezak Ahmed, Amos Ankotche, Kishwar Azad, Silver Bahendeka, Naby Baldé, Sunil M Jain, Jean Clovis Kalobu, Catherine Karekezi, Hero Kol, K M Prasannakumar, Sai Kham Leik, Jean Claude Mbanya, Maïmouna Ndour Mbaye, Babacar Niang, Vishnupriya Rao Paturi, Palany Raghupathy, Kaushik Ramaiya, Bipin Sethi, Bedowra Zabeen, Rifat Atun
Journal: The Lancet Diabetes & Endocrinology (2022)
Prevalence of synchronous neoplasia in patients with large pedunculated colorectal polyps
Authors: Ahmed El Rahyel, Rachel E. Lahr, Douglas K. Rex
Journal: Endoscopy (2022)

Large (≥ 20 mm) nonpedunculated colorectal lesions have high rates of synchronous neoplasia and advanced neoplasia. Synchronous neoplasia prevalence in patients with large pedunculated lesions is uncertain. We describe synchronous neoplasia in patients with large pedunculated colorectal polyps, using a cohort of patients with large nonpedunculated lesions as controls.This study was a retrospective assessment of a prospectively recorded database listing synchronous findings in patients with ≥ 20 mm colorectal lesions referred to a tertiary center for endoscopic resection.At least one synchronous precancerous lesion was identified in 66/78 patients with large pedunculated index lesions (84.6 %, 95 %CI 74.9-91.1) and 726/814 patients with large nonpedunculated index lesions (89.2 %, 95 %CI 87.1-91.3). Patients with a large pedunculated index lesion had mean of 4.8 synchronous conventional adenomas, 56.4 % had ≥ 1 synchronous high risk lesion (advanced adenoma or advanced serrated lesion), 48.7 % had ≥ 1 synchronous advanced conventional adenoma, and 19.2 % had a synchronous neoplastic lesion ≥ 20 mm. Compared with patients with nonpedunculated index lesions, patients with large pedunculated index lesions had comparable rates of synchronous polyps, adenomas, and sessile serrated lesions, and higher rates of synchronous adenomas with villous elements (15.6 % [95 %CI 13.3-18.3] vs. 26.9 % [95 %CI 18.3-37.7]; P = 0.01) and synchronous pedunculated polyps (9.5 % [95 %CI 7.6-11.7] vs. 33.3 % [95 %CI 23.8-44.4]; P < 0.001).In patients with large (≥ 20 mm) pedunculated colorectal lesions, rates of synchronous neoplasia and advanced synchronous neoplasia were high and comparable to or higher than rates of synchronous neoplasia in patients with large nonpedunculated colorectal lesions.
A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis
Authors: Xiaoliang Yu, Haikuo Ma, Bohan Li, Yuting Ji, Yayun Du, Siying Liu, Zhanhui Li, Yongjin Hao, Sheng Tian, Cong Zhao, Qian Du, Zhongqin Jin, Xueming Zhu, Yuanyuan Tian, Xin Chen, Xue Sun, Chengkui Yang, Fang Zhu, Jie Ju, Yunjing Zheng, Wei Zhang, Jingrui Wang, Tao Yang, Xinhui Wang, Jingjing Li, Xiangping Xu, Shujing Du, Haohao Lu, Feng Ma, Haibing Zhang, Yi Zhang, Xiaohu Zhang, Shaoyan Hu, Sudan He
Journal: Blood (2022)

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.
The burden of respiratory syncytial virus in healthy term-born infants in Europe: a prospective birth cohort study
Authors: Joanne G Wildenbeest, Marie-Noëlle Billard, Roy P Zuurbier, Koos Korsten, Annefleur C Langedijk, Peter M van de Ven, Matthew D Snape, Simon B Drysdale, Andrew J Pollard, Hannah Robinson, Terho Heikkinen, Steve Cunningham, Thomas O'Neill, Bishoy Rizkalla, Ana Dacosta-Urbieta, Federico Martinón-Torres, Marlies A van Houten, Louis J Bont
Journal: The Lancet Respiratory Medicine (2022)
GLP-1 Receptor Agonists and the Risk of Thyroid Cancer
Authors: Julien Bezin, Amandine Gouverneur, Marine Pénichon, Clément Mathieu, Renaud Garrel, Dominique Hillaire-Buys, Antoine Pariente, Jean-Luc Faillie
Journal: Diabetes Care (2022)

OBJECTIVE To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. RESEARCH DESIGN AND METHODS A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, &amp;gt;3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. RESULTS A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1–3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27–1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04–3.05). CONCLUSIONS In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1–3 years of treatment.
Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms
Authors: Christian Pecquet, Nicolas Papadopoulos, Thomas Balligand, Ilyas Chachoua, Amandine Tisserand, Gaëlle Vertenoeil, Audrey Nédélec, Didier Vertommen, Anita Roy, Caroline Marty, Harini Nivarthi, Jean-Philippe Defour, Mira El-Khoury, Eva Hug, Andrea Majoros, Erica Xu, Oleh Zagrijtschuk, Tudor E. Fertig, Daciana S. Marta, Heinz Gisslinger, Bettina Gisslinger, Martin Schalling, Ilaria Casetti, Elisa Rumi, Daniela Pietra, Chiara Cavalloni, Luca Arcaini, Mario Cazzola, Norio Komatsu, Yoshihiko Kihara, Yoshitaka Sunami, Yoko Edahiro, Marito Araki, Roman Lesyk, Veronika Buxhofer-Ausch, Sonja Heibl, Florence Pasquier, Violaine Havelange, Isabelle Plo, William Vainchenker, Robert Kralovics, Stefan N. Constantinescu
Journal: Blood (2022)

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.
Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial
Authors: Silvio E Inzucchi, Brian L Claggett, Muthiah Vaduganathan, Akshay S Desai, Pardeep S Jhund, Rudolf A de Boer, Adrian F Hernandez, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Subodh Verma, Yaling Han, Jose F Kerr Saraiva, Olof Bengtsson, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon
Journal: The Lancet Diabetes & Endocrinology (2022)
A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland
Authors: Anne Cathrine Baun Thuesen, Frederik Filip Stæger, Alba Kaci, Marie Holm Solheim, Ingvild Aukrust, Emil Jørsboe, Cindy G. Santander, Mette K. Andersen, Zilong Li, Arthur Gilly, Sara Elizabeth Stinson, Anette Prior Gjesing, Peter Bjerregaard, Michael Lynge Pedersen, Christina Viskum Lytken Larsen, Niels Grarup, Marit E. Jørgensen, Eleftheria Zeggini, Lise Bjørkhaug, Pål Rasmus Njølstad, Anders Albrechtsen, Ida Moltke, Torben Hansen
Journal: The Lancet Regional Health - Europe (2022)

The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population.Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact.We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = -232 pmol/L, βSD = -0.695, P = 4.43 × 10-4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10-6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10-3). The variant explained 2.5% of diabetes variance in Greenland.The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations.Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.
Phenol and Phthalate Effects on Thyroid Hormone Levels during Pregnancy: Relying on <i>In Vitro</i> Assays and Adverse Outcome Pathways to Inform an Epidemiological Analysis
Authors: Dorothy Nakiwala, Pamela D. Noyes, Patrice Faure, Benoît Chovelon, Christelle Corne, Anne Sophie Gauchez, Dorra Guergour, Sarah Lyon-Caen, Amrit K. Sakhi, Azemira Sabaredzovic, Cathrine Thomsen, Isabelle Pin, Rémy Slama, Claire Philippat
Journal: Environmental Health Perspectives (2022)

Background: Studies characterizing associations between phenols, phthalates and thyroid hormones during pregnancy produce inconsistent results. This divergence may be partly attributable to false positives due to multiple comparison testing of large numbers of chemicals, and measurement error as studies rely on small numbers of biospecimens despite high intra-individual variability in urinary chemical metabolite concentrations. Objectives: This study employs a priori chemical filtering and expanded urinary biomonitoring to evaluate associations between phenol/phthalate exposures and serum thyroid hormones assessed during pregnancy. Methods: A two-tiered approach was implemented: a) In vitro high-throughput screening results from the ToxCast/Tox21 database, as informed by a thyroid Adverse Outcome Pathway network, were evaluated to select phenols/phthalates with activity on known and putative molecular initiating events in the thyroid pathway; and b) Adjusted linear regressions were used to study associations between filtered compounds and serum thyroid hormones measured in 437 pregnant women recruited in Grenoble area (France) between 2014 and 2017. Phenol/phthalate metabolites were measured in repeated spot urine sample pools (median: 21 samples/women). Results: The ToxCast/Tox21 screening reduced the chemical set from 16 to 13 and the associated number of statistical comparisons by 19%. Parabens were negatively associated with free triiodothyronine (T3) and the T3/T4 (total thyroxine) ratio. Monobenzyl phthalate was positively associated with total T4 and negatively with the T3/T4 ratio. Effect modification by iodine status was detected for several compounds (among them ΣDEHP and mono-n-butyl phthalate) that were associated with some hormones among women with normal iodine levels. Conclusion: For these chemicals, screening for compounds with an increased likelihood for thyroid-related effects and relying on repeated urine samples to assess exposures improved the overall performance of multichemical analyses of thyroid disruption. This approach may improve future evaluations of human data for the thyroid pathway with implication for fetal health and may serve as a model for evaluating other toxicity outcomes. https://doi.org/10.1289/EHP10239